Systems and Methods to Image Intercellular and Intercompartmental Defects with Magnetic Resonance Imaging (MRI)

ABSTRACT

The invention provides systems and methods for providing a diagnostic examination to a patient, including, but not limited to a determination of the permeability of a patients&#39; body cavity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT ApplicationPCT/US2015/024309 entitled “Systems and Methods for detectingInterstitial cystitis” filed Apr. 3, 2015, which claims the benefit ofU.S. Provisional Application Ser. No. 61/974,964 entitled “Systems andMethods of Detecting Interstitial Cystitis” filed Apr. 3, 2014, and U.S.Provisional Application Ser. No. 62/062,339 entitled “Systems andMethods of Detecting Interstitial Cystitis” filed Oct. 10, 2014; and acontinuation-in-part of U.S. application Ser. No. 14/678,638 entitled“Systems and Methods for detecting Interstitial cystitis” filed Apr. 3,2015, which claims the benefit of U.S. Provisional Application Ser. No.61/974,964 entitled “Systems and Methods of Detecting InterstitialCystitis” filed Apr. 3, 2014, and U.S. Provisional Application Ser. No.62/062,339 entitled “Systems and Methods of Detecting InterstitialCystitis” filed Oct. 10, 2014, each of which are hereby incorporatedherein by reference in their entirety.

GOVERNMENT INTERESTS

Not Applicable

PARTIES TO A JOINT RESEARCH AGREEMENT

The presently claimed invention was made by or on behalf of the belowlisted parties to a joint research agreement. The joint researchagreement was in effect on or before the date the claimed invention wasmade and the claimed invention was made as a result of activitiesundertaken within the scope of the joint research agreement. The partiesto the joint research agreement are Lipella Pharmaceuticals Inc. and AriGoldberg.

BRIEF SUMMARY OF THE INVENTION

Embodiments herein are directed to methods for detecting patent foramenovale in a patient comprising: administering a T1-reducing contrastagent and a T2-reducing contrast agent to the patient; and imaging thepatient's heart; wherein diffusion of the T2 reducing contrast agentfrom the right atrium to the left atrium is indicative of patent foramenovale.

In some embodiments, the particle size of the T2-reducing contrast agentis larger than the particle size of the T1-reducing contrast agent. Insome embodiments, the T1-reducing agent, the T2-reducing agent, or acombination thereof further comprises an aqueous solvent. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered to the patient as a single composition; whereinthe single composition comprises the T1-reducing contrast agent and theT2-reducing contrast agent. In some embodiments, the single compositionfurther comprises an aqueous solvent. In some embodiments, theT1-reducing agent and the T2-reducing contrast agent are administered tothe patient as two separate compositions; wherein a first compositioncomprises the T1-reducing contrast agent; and wherein a secondcomposition comprises the T2-reducing contrast agent. In someembodiments, the two separate compositions each further comprise anaqueous solvent. In some embodiments, administering T1-reducing contrastagent and the T2-reducing contrast agent are completed simultaneously.

In some embodiments, imaging the patient's heart comprises imaging viamagnetic resonance imaging. In some embodiments, imaging the patient'sheart is performed within about 10 minutes of administration of theT1-reducing contrast agent and the T2-reducing contrast agent.

In some embodiments, the first T1-reducing contrast agent comprises agadolinium compound. In some embodiments, the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof. In some embodiments, the gadolinium compound is encapsulated inliposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof.

In some embodiments, the iron oxide is encapsulated in liposomes. Insome embodiments, administration of the T1-reducing contrast agent andthe T2-reducing contrast agent is achieved by administration to thepatient's cardiovascular system.

Some embodiments are directed to methods detecting patent foramen ovalein a patient comprising: imaging the patient after administering aT1-reducing contrast agent and a T2-reducing contrast agent to thepatient; wherein diffusion of the T2 reducing contrast agent from theright atrium to the left atrium is indicative of patent foramen ovale.

In some embodiments, the particle size of the T2-reducing contrast agentis larger than the particle size of the T1-reducing contrast agent. Insome embodiments, the T1-reducing agent, the T2-reducing agent, or acombination thereof further comprises an aqueous solvent.

In some embodiments, the T1-reducing contrast agent and the T2-reducingcontrast agent are administered to the patient as a single composition.In some embodiments, the single composition further comprises an aqueoussolvent. In some embodiments, the T1-reducing contrast agent and theT2-reducing contrast agent are administered to the patient as twoseparate compositions; wherein a first composition comprises theT1-reducing contrast agent and a second composition comprises theT2-reducing agent. In some embodiments, the two separate compositionseach further comprise an aqueous solvent. In some embodiments,administering T1-reducing contrast agent and the T2-reducing contrastagent are completed simultaneously. In some embodiments, imaging thepatient comprises imaging via magnetic resonance imaging. In someembodiments, imaging the patient is performed within about 10 minutes ofadministration of the T1-reducing contrast agent and the T2-reducingcontrast agent.

In some embodiments, the first T1-reducing contrast agent comprises agadolinium compound. In some embodiments, the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof. In some embodiments, the gadolinium compound is encapsulated inliposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof. In some embodiments, the ironoxide is encapsulated in liposomes.

In some embodiments, administration of the T1-reducing contrast agentand the T2-reducing contrast agent is achieved by administration to thepatient's cardiovascular system.

Some embodiments are directed to methods for detecting ischemicendocardium in a patient comprising: administering a T1-reducingcontrast agent and a T2-reducing contrast agent to the patient; andimaging the patient's heart; wherein diffusion of the T1 reducingcontrast agent across the endocardium is indicative of ischemicendocardium.

In some embodiments, the particle size of the T2-reducing contrast agentis larger than the particle size of the T1-reducing contrast agent. Insome embodiments, the T1-reducing agent, the T2-reducing agent, or acombination thereof further comprises an aqueous solvent. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered to the patient as a single composition; whereinthe single composition comprises the T1-reducing contrast agent and theT2-reducing contrast agent. In some embodiments, the single compositionfurther comprises an aqueous solvent. In some embodiments, theT1-reducing agent and the T2-reducing contrast agent are administered tothe patient as two separate compositions; wherein a first compositioncomprises the T1-reducing contrast agent; and wherein a secondcomposition comprises the T2-reducing contrast agent. In someembodiments, the two separate compositions each further comprise anaqueous solvent. In some embodiments, administering T1-reducing contrastagent and the T2-reducing contrast agent are completed simultaneously.

In some embodiments, imaging the patient's heart comprises imaging viamagnetic resonance imaging. In some embodiments, imaging the patient'sheart is performed within about 10 minutes of administration of theT1-reducing contrast agent and the T2-reducing contrast agent.

In some embodiments, the first T1-reducing contrast agent comprises agadolinium compound. In some embodiments, the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof. In some embodiments, the gadolinium compound is encapsulated inliposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof. In some embodiments, the ironoxide is encapsulated in liposomes.

In some embodiments, administration of the T1-reducing contrast agentand the T2-reducing contrast agent is achieved by administration to thepatient's cardiovascular system.

Some embodiments are directed to methods for detecting ischemicendocardium in a patient comprising: imaging the patient afteradministering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; wherein diffusion of the T1 reducing contrastagent across the endocardium is indicative of ischemic endocardium.

In some embodiments, the particle size of the T2-reducing contrast agentis larger than the particle size of the T1-reducing contrast agent. Insome embodiments, the T1-reducing agent, the T2-reducing agent, or acombination thereof further comprises an aqueous solvent. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered to the patient as a single composition. In someembodiments, the single composition further comprises an aqueoussolvent. In some embodiments, the T1-reducing contrast agent and theT2-reducing contrast agent are administered to the patient as twoseparate compositions; wherein a first composition comprises theT1-reducing contrast agent and a second composition comprises theT2-reducing agent. In some embodiments, the two separate compositionseach further comprise an aqueous solvent. In some embodiments,administering T1-reducing contrast agent and the T2-reducing contrastagent are completed simultaneously.

In some embodiments, imaging the patient comprises imaging via magneticresonance imaging. In some embodiments, imaging the patient is performedwithin about 10 minutes of administration of the T1-reducing contrastagent and the T2-reducing contrast agent.

In some embodiments, the first T1-reducing contrast agent comprises agadolinium compound. In some embodiments, the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof. In some embodiments, the gadolinium compound is encapsulated inliposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof. In some embodiments, the ironoxide is encapsulated in liposomes.

In some embodiments, administration of the T1-reducing contrast agentand the T2-reducing contrast agent is achieved by administration to thepatient's cardiovascular system.

BRIEF DESCRIPTION OF THE FIGURES

Not Applicable

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

Optical Isomers, Diastereomers, Geometric Isomers, and Tautomers.Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds according to the inventionpossess two or more asymmetric centers, they may additionally exist asdiastereomers. The present invention includes all such possiblestereoisomers as substantially pure resolved enantiomers, racemicmixtures thereof, as well as mixtures of diastereomers. The formulas areshown without a definitive stereochemistry at certain positions. Thepresent invention includes all stereoisomers of such formulas andpharmaceutically acceptable salts thereof. Diastereoisomeric pairs ofenantiomers may be separated by, for example, fractional crystallizationfrom a suitable solvent, and the pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid or base as a resolvingagent or on a chiral HPLC column. Further, any enantiomer ordiastereomer of a compound of the general formula may be obtained bystereospecific synthesis using optically pure starting materials orreagents of known configuration.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “fibroblast” is a reference to one or more fibroblasts and equivalentsthereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Administering” when used in conjunction with the imaging compositionscontaining the T1-reducing contrast agents, T2-reducing contrast agents,or combinations thereof, described herein means to administer the agent,agents or compositions directly into, or onto a target body cavity or toadminister the agent, agents or compositions to a patient whereby theagent or agents impacts the body cavity to which it is targeted. Thus,as used herein, the term “administering”, when used in conjunction withany agent, agents, or compositions described herein, can include, but isnot limited to, providing an agent, agents, or compositions into or ontothe target body cavity; providing an agent, agents, or compositionsystemically to a patient by, e.g., intravenous injection whereby theagent or agents reaches the target tissue; administering the agent,agents or compositions described herein to the lumen of a body cavity.“Administering” a composition may be accomplished by injection,instillation, catheterization, or by either method in combination withother known techniques. “Administering” agent, agents or compositionsdescribed herein to the lumen of a body cavity can also be achievedthrough a natural opening to the body cavity. For example, the agent,agents or compositions described herein can be administered to the lumenof a blood vessel via intravenous injection. In yet another example theagent, agents or compositions described herein can be administered tothe lumen of the gastrointestinal tract via oral administration.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “liposome” generally refers to spherical or roughly sphericalparticles containing an internal cavity. The walls of liposomes caninclude a bilayer of lipids. These lipids can be phospholipids. Numerouslipids and/or phospholipids may be used to make liposomes. One exampleare amphipathic lipids having hydrophobic and polar head group moietieswhich may form spontaneously into bilayer vesicles in water, asexemplified by phospholipids, or which may be stably incorporated intolipid bilayers, with their hydrophobic moiety in contact with theinterior, hydrophobic region of the bilayer membrane, and their polarhead group moiety oriented toward the exterior, polar surface of themembrane.

The term “body cavity” refers to any fluid filled space in amulticellular organism including but not limited the cardiovascularsystem, the heart, blood vessels, lymph vessels, coelom, pericardialcavity, pericardium, intraembryonic coelom, extraembryonic coelom,chorionic cavity, dorsal cavity, ventral cavity, thoracic cavity,abdominopelvic cavity, cranial cavity, spinal cavity (or vertebralcavity), a pleural cavity, superior mediastinum, thoracic cavity,abdominal cavity, pelvic cavity. abdominopelvic cavity, urinary bladder,kidneys, ureters, gastrointestinal tract, stomach, intestines, liver,gallbladder, pancreas, anus, reproductive system or any combinationthereof. In some embodiments, the body cavity is naturally fluid filled.In some embodiments, the body cavity is artificially fluid filled.

The term “cardiovascular system” refers to a closed organ system made upof the heart and blood vessels (including arteries, veins andcapillaries, coronary vessels, portal veins) of a vertebrate organismsuch as a mammal, and more preferably a human.

The term “gastrointestinal tract” refers to a an organ system made up ofthe stomach and intestines (including the small and large intestines,appendix) of a vertebrate organism such as a mammal, and more preferablya human. The gastrointestinal tract may also include all structuresbetween the mouth and the anus (including the esophagus, stomach, smalland large intestines, appendix, and rectum) of a vertebrate organismsuch as a mammal, and more preferably a human.

As used herein, the term “lumen” refers to the interior space of a bodycavity. In some embodiment, the lumen of a body cavity is enclosed by aluminal wall, the porosity of which can be measured using the methodsand compositions described herein.

As used herein, the term “contrast agent” refers to a compound ormolecule that can be used in the imaging of body cavity and whichaffects and/or enhances the contrast of structures and/or fluids in thebody. In some embodiments, the term “contrast agent” refers to aparamagnetic and/or superparamagnetic compound or molecule that can beused in the imaging of body cavity. In some embodiments, a particularcontrast agent may have a T1-reducing contrast effect (spin-spinrelaxation), a T2-contrast reducing effect (spin-lattice relaxation) ora combination thereof. As used herein, one or more contrast agents maybe incorporated into a composition which may then be administered to apatient to image a body cavity.

The present disclosure generally relates to systems and methods forproviding a diagnostic examination to a patient, including, but notlimited to a determination of the permeability of a patients' bodycavity. In some embodiments, such diagnostic examination may generallyinclude measurement of patency and/or porosity of the body cavity byobserving the diffusion of a non-invasively detectable molecular agentacross the luminal surface of the body cavity. In some embodiments, suchdiagnostic examination may generally include measurement ofpermeability, patency and/or porosity of the body cavity by observingthe diffusion of a non-invasively detectable molecular agent out thelumen of the body cavity. In some embodiments, the systems and methodsdescribed herein may be used for determining altered permeability of thelining of other body cavities, such as, for example, cardiovascularsystem, blood vessels, the heart, the vagina, gut, sinus and oralcavities or a combination thereof. Some embodiments are directed to amethod for measuring the permeability of a body cavity in a patient.

In some embodiments, present disclosure generally relates to systems andmethods for providing a diagnostic examination to a patient, including,but not limited to detection of patent foramen ovale (PFO). In someembodiments, such diagnostic examination may generally includemeasurement of patency and/or porosity of the body cavity by observingthe diffusion of a non-invasively detectable molecular agent across theluminal surface of the body cavity. In some embodiments, such diagnosticexamination may generally include measurement of patency and/or porosityof the body cavity by observing the diffusion of a non-invasivelydetectable molecular agent out the lumen of the body cavity. In someembodiments, the systems and methods described herein may also be usedfor determining altered permeability of the lining of other bodycavities, such as, for example, the vagina, gut, sinus and oralcavities. Some embodiments are directed to a diagnostic examination of apatient's heart. In particular embodiments, such diagnostic examinationmay generally include detection of PFO, ischemic endocardium or acombination thereof. In some embodiments, the systems and methodsdescribed herein may be used for diagnosing PFO. In some embodiments,the systems and methods described herein may be used for diagnosingischemic endocardium.

The methods and contrast agents described herein may also be utilized inthe detection and diagnosis of diseases caused by, or associated with,pathologic breakdown of the inner layers of arterial walls, such as, butnot limited to: post-embolic or pre-hemorrhagic stroke breakdown of theblood-brain-barrier (BBB), vasculitis, ruptured atherosclerotic plaque,diabetic vasculopathy, inflammation, vasculitis, autoimmune diseases,infection, cancer, septic shock, or a combination thereof.

PFO is characterized by a hole located in the septum of the heartbetween the right and left atria, typically about 1 mm in size. PFO is aknown cause of embolic stroke where small blood clots may bypass thefilter of the lung capillary bed and become ejected out the heart intothe aorta and through the systemic and cerebral circulation. The PFOworks like a flap valve, only opening during certain conditions whenthere is more pressure inside the chest. This increased pressure occurswhen a subjects strain while having, for example, a bowel movement,cough, or sneeze. If the resulting pressure is great enough, blood maytravel from the right atrium to the left atrium. If there is a clot orparticles in the blood traveling in the right side of the heart, it cancross the PFO, enter the left atrium, and travel out of the heart and tothe brain (causing a stroke) or into a coronary artery (causing a heartattack).

Embodiments herein are directed to methods for detecting PFO in apatient comprising: administering a T1-reducing contrast agent and aT2-reducing contrast agent to the patient; and imaging the patient'sheart; wherein diffusion of the T2 reducing contrast agent into the leftheart is indicative of PFO.

In some embodiments, the T1 reducing agent is able to pass freelythrough the circulatory system and enter the left heart cavity, whereasthe T2 reducing agent is filtered by the lung capillaries such that in asubject without PFO, only the T1 reducing agent is able to enter theleft heart cavity. Conversely, in a subject with PFO, the T2 reducingagent will be able to enter the left heart cavity via the hole(s) in theheart between the right and left atria. The result is that, in a healthysubject, only the T1 reducing agent will be present in the left heartwhereas with a subject with PFO both the T1 reducing agent and T2reducing agent will be present in the left heart.

Some embodiments are directed to methods for detecting PFO in a patientcomprising: imaging the patient's heart after administering aT1-reducing contrast agent and a T2-reducing contrast agent to thepatient; wherein diffusion of the T2 reducing contrast agent from theright atrium to the left atrium is indicative of PFO. In someembodiments, diffusion of the T2 reducing contrast agent from the rightatrium to the left atrium is indicative of PFO. In some embodiments, theabsence of the PFO prevents the T2 reducing contrast agent fromdiffusing from the right atrium to the left atrium. In some embodiments,the T1 reducing contrast agent is able to circulate freely through thevasculature due to its small size. In some embodiments, the particlesize of the T2-reducing contrast agent is larger than the particle sizeof the T1-reducing contrast agent. In some embodiments, the averageparticle size of the T2-reducing contrast agent is larger than theaverage particle size of the T1-reducing contrast agent. In someembodiments, the particle size of the majority of the particlescomprising the T2-reducing contrast agent is larger than the particlesize of the majority of the particles comprising the T1-reducingcontrast agent. In some embodiments, the particle size of about 90% toabout 99% of the particles comprising the T2-reducing contrast agent islarger than the particle size of about 90% to about 99% of the particlescomprising the T1-reducing contrast agent. In some embodiments, theparticle size of about 90% of the particles comprising the T2-reducingcontrast agent is larger than the particle size of about 90% of theparticles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 95% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about95% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 99% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about99% of the particles comprising the T1-reducing contrast agent.

Some embodiments are directed to the use of imaging compositionscomprising a T1-reducing contrast agent and T2-reducing contrast agent,which may be administered to cardiovascular system of a subject, whereeach of the contrast agents have different size particles and havedifferent contrast effects. For example, relatively large iron oxideparticles (having approximate diameters from about 3.5 and about 80microns) will reduce local T2 (spin-spin relaxation) times, andrelatively small gadolinium chelate particles (having approximatediameters from about 7 to about 11 angstroms) will reduce local T1(spin-lattice relaxation) times. Without wishing to be bound by theory,the use of particles with differing particle size and contrast effectresults in a differential distribution in the subjects' cardiovascularsystem due to filtration by lung capillaries that prevent largerparticles from entering the right side of the heart and to the rest ofthe body via the systemic arteries. In a subject without PFO, thesmaller particles (i.e. gadolinium particles) can diffuse throughout thecardiovascular system, whereas the larger particles (i.e. iron oxideparticles) are restricted to the right side of the heart and pulmonaryarteries and are prevented from diffusing past the lungs due to theirlarger size. In yet other embodiments, in a permeable body cavity, thesmaller particles (i.e. gadolinium particles) can diffuse out of thelumen of the body cavity into the luminal wall and surrounding tissue,whereas the larger particles (i.e. iron oxide particles) remain in thelumen. Because iron and gadolinium have opposite effects on magneticresonance imaging signal intensity, once the smaller particles havediffused across the luminal surface of the body cavity, or out of thelumen of the body cavity, they can now be visualized withoutinterference or masking by the contrast effect of the larger particles.For example, iron oxide particles reduce image signal intensity withintheir immediate vicinity, whereas the gadolinium particles increasesignal intensity within their immediate vicinity and the result of bothparticles being present in the lumen of a body cavity is an overalldecrease in signal intensity masking the contrast effect of thegadolinium particle. Therefore, when the lumen of a body cavity isintact and impermeable, the contrast effect of the smaller gadoliniumparticle is masked by the contrast effect of the larger iron particles.

In some embodiments, the relative concentrations of the T1-reducingcontrast agent and T2-reducing contrast agent used may be optimized sothat the concentration of the T2-reducing contrast agent (i.e. ironoxide particles) is strong enough to completely mask the effect of theT1-reducing contrast agent (i.e. gadolinium) within the lumen of a bloodvessel. Thus, when the blood vessel is impermeable, there is virtuallyno signal, or image intensity, present within the lumen of the bloodvessel. However, when administered to a permeable blood vessel, theT1-reducing contrast agent, (i.e. gadolinium chelate) is able to diffuseacross the luminal surface of the blood vessel, or out of the lumen ofthe blood vessel, and escape the vicinity of the T2-reducing contrastagent (i.e. iron oxide particles), which are too large to diffuse acrossthe luminal surface of the blood vessel, or out of the lumen of theblood vessel. In some embodiments, the result is that the wall of apermeable blood vessel will appear as a bright ring on an MRI image,including a slice selective MRI image that includes the blood vessel andsurrounding tissue, whereas in the case of an impermeable blood vessel,the wall of said blood vessel will not be visible on an MRI image,including a slice selective MRI image that includes the blood vessel andsurrounding tissue. In other embodiments, in the case of an impermeableblood vessel, the wall of said blood vessel will be visible on an MRIimage, including a slice selective MRI image that includes the bloodvessel and surrounding tissue, but will not have the bright ringenhancement of the T1-reducing contrast agent.

In some embodiments, the methods of detecting PFO described herein mayadditionally, or alternatively, be utilized to measure the permeabilityof the luminal lining of a body cavity, the permeability of the luminalsurface of a body cavity or a combination thereof. In some embodiments,detecting PFO described herein may include measuring the permeability ofthe luminal lining of a body cavity, the permeability of the luminalsurface of a body cavity or a combination thereof.

Embodiments herein are directed to methods for detecting ischemicendocardium in a patient comprising: administering a T1-reducingcontrast agent and a T2-reducing contrast agent to the patient; andimaging the patient's heart; wherein diffusion of the T1 reducingcontrast agent into the left heart is indicative of ischemicendocardium.

The endocardium is the thin inner cellular lining of the heart cavities,including the left ventricle. Sufficient ischemia to a segment of theleft ventricle results in a breakdown of the cells and cell-celljunctions in the endocardium.

In some embodiments, ischemic endocardium can be detected by measurementof the permeability of the endocardium in a patient comprising:administering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; and imaging the patient's heart; wherein diffusionof the T1 reducing contrast agent across the luminal surface of theendocardium is indicative of permeability, which in turn may beindicative of ischemic endocardium. In some embodiments, diffusion ofthe T1 reducing contrast agent out of the lumen of the endocardium isindicative of permeability, which in turn may be indicative of ischemicendocardium.

Some embodiments are directed to methods for detecting ischemicendocardium in a patient comprising: imaging the patient's heart afteradministering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; wherein diffusion of the T1 reducing contrastagent across the luminal surface of the endocardium is indicative ofpermeability, which in turn may be indicative of ischemic endocardium.In some diffusion of the T1 reducing contrast agent out of the lumen ofthe endocardium is indicative of permeability, which in turn may beindicative of ischemic endocardium. In some embodiments, the particlesize of the T2-reducing contrast agent is larger than the particle sizeof the T1-reducing contrast agent. In some embodiments, the averageparticle size of the T2-reducing contrast agent is larger than theaverage particle size of the T1-reducing contrast agent. In someembodiments, the particle size of the majority of the particlescomprising the T2-reducing contrast agent is larger than the particlesize of the majority of the particles comprising the T1-reducingcontrast agent. In some embodiments, the particle size of about 90% toabout 99% of the particles comprising the T2-reducing contrast agent islarger than the particle size of about 90% to about 99% of the particlescomprising the T1-reducing contrast agent. In some embodiments, theparticle size of about 90% of the particles comprising the T2-reducingcontrast agent is larger than the particle size of about 90% of theparticles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 95% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about95% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 99% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about99% of the particles comprising the T1-reducing contrast agent.

Some embodiments are directed to the use of imaging compositionscomprising a T1-reducing contrast agent and T2-reducing contrast agent,which may be administered to the lumen of a body cavity for detectingischemic endocardium, where each of the contrast agents have differentsize particles and have different contrast effects. For example,relatively large iron oxide particles (having approximate diameters fromabout 3.5 and about 80 microns) will reduce local T2 (spin-spinrelaxation) times, and relatively small gadolinium chelate particles(having approximate diameters from about 7 to about 11 angstroms) willreduce local T1 (spin-lattice relaxation) times. Without wishing to bebound by theory, the use of particles with differing particle size andcontrast effect results in a differential distribution in lumen andluminal wall of the endocardium depending on whether the endocardium ispermeable. In a permeable body cavity, the smaller particles (i.e.gadolinium particles) can diffuse across the luminal surface of theendocardium into the luminal wall and surrounding tissue, whereas thelarger particles (i.e. iron oxide particles) remain in the lumen. In yetother embodiments, in a permeable endocardium, the smaller particles(i.e. gadolinium particles) can diffuse out of the lumen of theendocardium into the luminal wall and surrounding tissue, whereas thelarger particles (i.e. iron oxide particles) remain in the lumen.Because iron and gadolinium have opposite effects on magnetic resonanceimaging signal intensity, once the smaller particles have diffusedacross the luminal surface of the endocardium, or out of the lumen ofthe endocardium, they can now be visualized without interference ormasking by the contrast effect of the larger particles. For example,iron oxide particles reduce image signal intensity within theirimmediate vicinity, whereas the gadolinium particles increase signalintensity within their immediate vicinity and the result of bothparticles being present in the lumen of the endocardium is an overalldecrease in signal intensity masking the contrast effect of thegadolinium particle. Therefore, when the lumen of the endocardium isintact and impermeable, the contrast effect of the smaller gadoliniumparticle is masked by the contrast effect of the larger iron particles.

In some embodiments, the relative concentrations of the T1-reducingcontrast agent and T2-reducing contrast agent used may be optimized sothat the concentration of the T2-reducing contrast agent (i.e. ironoxide particles) is strong enough to completely mask the effect of theT1-reducing contrast agent (i.e. gadolinium) within the lumen of theendocardium. Thus, when the endocardium is impermeable, there isvirtually no signal, or image intensity, present within the lumen of theendocardium. However, when administered to a permeable endocardium, theT1-reducing contrast agent, (i.e. gadolinium chelate) is able to diffuseacross the luminal surface of the endocardium, or out of the lumen ofthe endocardium, and escape the vicinity of the T2-reducing contrastagent (i.e. iron oxide particles), which are too large to diffuse acrossthe luminal surface of the endocardium, or out of the lumen of theendocardium. In some embodiments, the result is that the wall of apermeable endocardium will appear as a bright ring on an MRI image,including a slice selective MRI image that includes the endocardium andsurrounding tissue, whereas in the case of an impermeable endocardium,the wall of said endocardium will not be visible on an MRI image,including a slice selective MRI image that includes the endocardium andsurrounding tissue. In other embodiments, in the case of an impermeableendocardium, the wall of said endocardium will be visible on an MRIimage, including a slice selective MRI image that includes theendocardium and surrounding tissue, but will not have the bright ringenhancement of the T1-reducing contrast agent.

Embodiments herein are directed to methods for detecting a conditionassociated with the pathological breakdown of the layers of epithelialcells and cell junctions that line the gastrointestinal tract in apatient comprising: administering a T1-reducing contrast agent and aT2-reducing contrast agent to the patient; and imaging the patient'sgastrointestinal tract; wherein diffusion of the T1 reducing contrastagent into the left heart is indicative of a condition associated withthe pathological breakdown of the layers of epithelial cells and celljunctions that line the gastrointestinal tract. In some embodiments, theT1-reducing contrast agent and the T2-reducing contrast agent areadministered orally. In some embodiments, conditions associated with thepathological breakdown of the layers of epithelial cells and celljunctions that line the gastrointestinal tract include but are notlimited to inflammatory bowel disease, gastric/duodenal ulcer disease,celiac disease, or any combination thereof.

In some embodiments, a condition associated with the pathologicalbreakdown of the layers of epithelial cells and cell junctions that linethe gastrointestinal tract can be detected by measurement of thepermeability of the gastrointestinal tract lumen in a patientcomprising: administering a T1-reducing contrast agent and a T2-reducingcontrast agent to the patient; and imaging the patient'sgastrointestinal tract; wherein diffusion of the T1 reducing contrastagent across the luminal surface of the gastrointestinal tract isindicative of permeability, which in turn may be indicative of acondition associated with the pathological breakdown of the layers ofepithelial cells and cell junctions that line the gastrointestinaltract. In some embodiments, diffusion of the T1 reducing contrast agentout of the lumen of the gastrointestinal tract is indicative ofpermeability, which in turn may be indicative of a condition associatedwith the pathological breakdown of the layers of epithelial cells andcell junctions that line the gastrointestinal tract. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered orally. In some embodiments conditions associatedwith the pathological breakdown of the layers of epithelial cells andcell junctions that line the gastrointestinal tract include but are notlimited to inflammatory bowel disease, gastric/duodenal ulcer disease,celiac disease or combinations thereof.

Some embodiments are directed to methods for detecting a conditionassociated with the pathological breakdown of the layers of epithelialcells and cell junctions that line the gastrointestinal tract in apatient comprising: imaging the patient's gastrointestinal tract afteradministering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; wherein diffusion of the T1 reducing contrastagent across the luminal surface of the gastrointestinal tract isindicative of permeability, which in turn may be indicative of acondition associated with the pathological breakdown of the layers ofepithelial cells and cell junctions that line the gastrointestinaltract. In some diffusion of the T1 reducing contrast agent out of thelumen of the gastrointestinal tract is indicative of permeability, whichin turn may be indicative of a condition associated with thepathological breakdown of the layers of epithelial cells and celljunctions that line the gastrointestinal tract. In some embodiments, theparticle size of the T2-reducing contrast agent is larger than theparticle size of the T1-reducing contrast agent. In some embodiments,the average particle size of the T2-reducing contrast agent is largerthan the average particle size of the T1-reducing contrast agent. Insome embodiments, the particle size of the majority of the particlescomprising the T2-reducing contrast agent is larger than the particlesize of the majority of the particles comprising the T1-reducingcontrast agent. In some embodiments, the particle size of about 90% toabout 99% of the particles comprising the T2-reducing contrast agent islarger than the particle size of about 90% to about 99% of the particlescomprising the T1-reducing contrast agent. In some embodiments, theparticle size of about 90% of the particles comprising the T2-reducingcontrast agent is larger than the particle size of about 90% of theparticles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 95% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about95% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 99% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about99% of the particles comprising the T1-reducing contrast agent. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered orally. In some embodiments conditions associatedwith the pathological breakdown of the layers of epithelial cells andcell junctions that line the gastrointestinal tract include but are notlimited to inflammatory bowel disease, gastric/duodenal ulcer disease,celiac disease, or combinations thereof.

Some embodiments are directed to the use of imaging compositionscomprising a T1-reducing contrast agent and T2-reducing contrast agent,which may be administered to the lumen of a body cavity for detecting acondition associated with the pathological breakdown of the layers ofepithelial cells and cell junctions that line the gastrointestinaltract, where each of the contrast agents have different size particlesand have different contrast effects. For example, relatively large ironoxide particles (having approximate diameters from about 3.5 and about80 microns) will reduce local T2 (spin-spin relaxation) times, andrelatively small gadolinium chelate particles (having approximatediameters from about 7 to about 11 angstroms) will reduce local T1(spin-lattice relaxation) times. Without wishing to be bound by theory,the use of particles with differing particle size and contrast effectresults in a differential distribution in lumen and luminal wall of thegastrointestinal tract depending on whether the lumen is permeable. In apermeable body cavity, the smaller particles (i.e. gadolinium particles)can diffuse across the luminal surface of the gastrointestinal tractinto the luminal wall and surrounding tissue, whereas the largerparticles (i.e. iron oxide particles) remain in the lumen. In yet otherembodiments, in a permeable gastrointestinal tract, the smallerparticles (i.e. gadolinium particles) can diffuse out of the lumen ofthe gastrointestinal tract into the luminal wall and surrounding tissue,whereas the larger particles (i.e. iron oxide particles) remain in thelumen. Because iron and gadolinium have opposite effects on magneticresonance imaging signal intensity, once the smaller particles havediffused across the luminal surface of the gastrointestinal tract, orout of the lumen of the endocardium, they can now be visualized withoutinterference or masking by the contrast effect of the larger particles.For example, iron oxide particles reduce image signal intensity withintheir immediate vicinity, whereas the gadolinium particles increasesignal intensity within their immediate vicinity and the result of bothparticles being present in the lumen of the gastrointestinal tract is anoverall decrease in signal intensity masking the contrast effect of thegadolinium particle. Therefore, when the lumen of the gastrointestinaltract is intact and impermeable, the contrast effect of the smallergadolinium particle is masked by the contrast effect of the larger ironparticles. In some embodiments, the compositions comprising aT1-reducing contrast agent and T2-reducing contrast agent areadministered orally. In some embodiments condition associated with thepathological breakdown of the layers of epithelial cells and celljunctions that line the gastrointestinal tract include but are notlimited to inflammatory bowel disease, gastric/duodenal ulcer disease,celiac disease, or combinations thereof.

In some embodiments, the relative concentrations of the T1-reducingcontrast agent and T2-reducing contrast agent used may be optimized sothat the concentration of the T2-reducing contrast agent (i.e. ironoxide particles) is strong enough to completely mask the effect of theT1-reducing contrast agent (i.e. gadolinium) within the lumen of thegastrointestinal tract. Thus, when the endocardium is impermeable, thereis virtually no signal, or image intensity, present within the lumen ofthe gastrointestinal tract. However, when administered to a permeablegastrointestinal tract, the T1-reducing contrast agent, (i.e. gadoliniumchelate) is able to diffuse across the luminal surface of thegastrointestinal tract, or out of the lumen of the gastrointestinaltract, and escape the vicinity of the T2-reducing contrast agent (i.e.iron oxide particles), which are too large to diffuse across the luminalsurface of the gastrointestinal tract, or out of the lumen of thegastrointestinal tract. In some embodiments, the result is that the wallof a permeable gastrointestinal tract will appear as a bright ring on anMRI image, including a slice selective MRI image that includes thegastrointestinal tract and surrounding tissue, whereas in the case of animpermeable gastrointestinal tract, the wall of said endocardium willnot be visible on an MRI image, including a slice selective MRI imagethat includes the gastrointestinal tract and surrounding tissue. Inother embodiments, in the case of an impermeable gastrointestinal tract,the wall of said gastrointestinal tract will be visible on an MRI image,including a slice selective MRI image that includes the gastrointestinaltract and surrounding tissue, but will not have the bright ringenhancement of the T1-reducing contrast agent.

Embodiments herein are directed to methods for measuring thepermeability of a body cavity in a patient comprising: administering aT1-reducing contrast agent and a T2-reducing contrast agent to thepatient; and imaging the patient; wherein diffusion of the T1 reducingcontrast agent across the luminal surface of the body cavity isindicative of permeability. In some embodiments, diffusion of the T1reducing contrast agent out of the lumen of the body cavity isindicative of permeability.

In some embodiments, the methods of measuring the permeability of a bodycavity described herein may additionally, or alternatively, be utilizedto measure the permeability of the luminal lining of a body cavity, thepermeability of the luminal surface of a body cavity or a combinationthereof. In some embodiments, measuring the permeability of a bodycavity described herein may include measuring the permeability of theluminal lining of a body cavity, the permeability of the luminal surfaceof a body cavity or a combination thereof.

Some embodiments are directed to methods for measuring the permeabilityof a body cavity in a patient comprising: imaging the patient afteradministering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; wherein diffusion of the T1 reducing contrastagent across the luminal surface of the body cavity is indicative ofpermeability. In some diffusion of the T1 reducing contrast agent out ofthe lumen of the body cavity is indicative of permeability. In someembodiments, the particle size of the T2-reducing contrast agent islarger than the particle size of the T1-reducing contrast agent. In someembodiments, the average particle size of the T2-reducing contrast agentis larger than the average particle size of the T1-reducing contrastagent. In some embodiments, the particle size of the majority of theparticles comprising the T2-reducing contrast agent is larger than theparticle size of the majority of the particles comprising theT1-reducing contrast agent. In some embodiments, the particle size ofabout 90% to about 99% of the particles comprising the T2-reducingcontrast agent is larger than the particle size of about 90% to about99% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 90% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about90% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 95% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about95% of the particles comprising the T1-reducing contrast agent. In someembodiments, the particle size of about 99% of the particles comprisingthe T2-reducing contrast agent is larger than the particle size of about99% of the particles comprising the T1-reducing contrast agent.

Some embodiments are directed to the use of imaging compositionscomprising a T1-reducing contrast agent and T2-reducing contrast agent,which may be administered to the lumen of a body cavity, where each ofthe contrast agents have different size particles and have differentcontrast effects. For example, relatively large iron oxide particles(having approximate diameters from about 3.5 and about 80 microns) willreduce local T2 (spin-spin relaxation) times, and relatively smallgadolinium chelate particles (having approximate diameters from about 7to about 11 angstroms) will reduce local T1 (spin-lattice relaxation)times. Without wishing to be bound by theory, the use of particles withdiffering particle size and contrast effect results in a differentialdistribution in lumen and luminal wall of a body cavity depending onwhether the body cavity is permeable. In a permeable body cavity, thesmaller particles (i.e. gadolinium particles) can diffuse across theluminal surface of the body cavity into the luminal wall and surroundingtissue, whereas the larger particles (i.e. iron oxide particles) remainin the lumen. In yet other embodiments, in a permeable body cavity, thesmaller particles (i.e. gadolinium particles) can diffuse out of thelumen of the body cavity into the luminal wall and surrounding tissue,whereas the larger particles (i.e. iron oxide particles) remain in thelumen. Because iron and gadolinium have opposite effects on magneticresonance imaging signal intensity, once the smaller particles havediffused across the luminal surface of the body cavity, or out of thelumen of the body cavity, they can now be visualized withoutinterference or masking by the contrast effect of the larger particles.For example, iron oxide particles reduce image signal intensity withintheir immediate vicinity, whereas the gadolinium particles increasesignal intensity within their immediate vicinity and the result of bothparticles being present in the lumen of a body cavity is an overalldecrease in signal intensity masking the contrast effect of thegadolinium particle. Therefore, when the lumen of a body cavity isintact and impermeable, the contrast effect of the smaller gadoliniumparticle is masked by the contrast effect of the larger iron particles.

In some embodiments, the relative concentrations of the T1-reducingcontrast agent and T2-reducing contrast agent used may be optimized sothat the concentration of the T2-reducing contrast agent (i.e. ironoxide particles) is strong enough to completely mask the effect of theT1-reducing contrast agent (i.e. gadolinium) within the lumen of a bodycavity. Thus, when the body cavity is impermeable, there is virtually nosignal, or image intensity, present within the lumen of the body cavity.However, when administered to a permeable body cavity, the T1-reducingcontrast agent, (i.e. gadolinium chelate) is able to diffuse across theluminal surface of the body cavity, or out of the lumen of the bodycavity, and escape the vicinity of the T2-reducing contrast agent (i.e.iron oxide particles), which are too large to diffuse across the luminalsurface of the body cavity, or out of the lumen of the body cavity. Insome embodiments, the result is that the wall of a permeable body cavitywill appear as a bright ring on an MRI image, including a sliceselective MRI image that includes the body cavity and surroundingtissue, whereas in the case of an impermeable body cavity, the wall ofsaid cavity will not be visible on an MRI image, including a sliceselective MRI image that includes the body cavity and surroundingtissue. In other embodiments, in the case of an impermeable body cavity,the wall of said cavity will be visible on an MRI image, including aslice selective MRI image that includes the body cavity and surroundingtissue, but will not have the bright ring enhancement of the T1-reducingcontrast agent.

In various embodiments, the T1-reducing contrast agent and T2-reducingcontrast agent have differing contrast effects. For example, in someembodiments, the effects of the T1-reducing contrast agent may bedisambiguated from the effects of the T2-reducing contrast agent suchthat a person skilled in the art can detect a difference between theeffects of the T1-reducing contrast agent and the T2-reducing contrastagent when viewing the results of the diagnostic imaging describedherein. Different contrast effects may be visible, for example, when theT1-reducing contrast agent contains a plurality of molecules that aresmaller in diameter relative to the diameter of the plurality ofmolecules contained in the T2-reducing contrast agent. Differentcontrast effects may be visible, for example, when the T1-reducingcontrast agent contains a plurality of molecules that are smaller inaverage diameter relative to the average diameter of the plurality ofmolecules contained in the T2-reducing contrast agent. Differentcontrast effects may also be visible, for example, when the T1-reducingcontrast agent affects a T1-weighted MRI image and the T2-reducingcontrast agent affects a T2-weighted MRI image. In some embodiments, theT1-reducing contrast agent and the T2-reducing contrast agent havedifferent particle sizes. In some embodiments, the T1-reducing contrastagent has a smaller particle size than the T2-reducing contrast agent.In some embodiments, the T1-reducing contrast agent has a particle sizethat enables it to move out of lumen of a permeable body cavity. Inother embodiments, for example, the T2-reducing contrast agent containsa plurality of molecules that are smaller in diameter relative to thediameter of the plurality of molecules contained in the T1-reducingcontrast agent. Different contrast effects may be visible, for example,when the T2-reducing contrast agent contains a plurality of moleculesthat are smaller in average diameter relative to the average diameter ofthe plurality of molecules contained in the T1-reducing contrast agent.In some embodiments, the T2-reducing contrast agent has a smallerparticle size than the T1-reducing contrast agent. In some embodiments,the T2-reducing contrast agent has a particle size that enables it tomove out of lumen of a permeable body cavity. In some embodiments, theT2-reducing contrast agent has a particle size that enables it to moveout of lumen of a permeable blood vessel.

In some embodiments, the T1-reducing contrast agent exhibitspredominantly T1-reducing contrast effects. In some embodiments, theT1-reducing contrast agent may also exhibit T2-reducing contrasteffects. In some embodiments, the T2-reducing contrast effects of theT1-reducing contrast agent are concentration dependent. In someembodiments, the T2-reducing contrast effects of the T1-reducingcontrast agent are concentration dependent. In some embodiments, theT1-reducing contrast agent may exhibit T2-reducing effects at highconcentrations. In some embodiments, the T2-reducing contrast agentexhibits predominantly T2-reducing contrast effects. In someembodiments, the T2-reducing contrast agent may also exhibit T1-reducingcontrast effects. In some embodiments, the T1-reducing contrast effectsof the T2-reducing contrast agent are concentration dependent. In someembodiments, the T2-reducing contrast effects of the T2-reducingcontrast agent are concentration dependent. In some embodiments, theT2-reducing contrast agent may exhibit T1-reducing effects at highconcentrations.

In some embodiments, the T1-reducing agent, the T2-reducing agent, or acombination thereof further comprises an aqueous solvent. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent are administered to the patient as a single composition; whereinthe single composition comprises the T1-reducing contrast agent and theT2-reducing contrast agent. In some embodiments, the single compositionfurther comprises an aqueous solvent. In some embodiments, theT1-reducing agent and the T2-reducing contrast agent are administered tothe patient as two separate compositions; wherein a first compositioncomprises the T1-reducing contrast agent; and wherein a secondcomposition comprises the T2-reducing contrast agent. In someembodiments, the T1-reducing agent and the T2-reducing contrast agentare administered to the patient as two separate compositions; wherein afirst composition comprises the T2-reducing contrast agent; and whereina second composition comprises the T-1 reducing contrast agent. In someembodiments, the two separate compositions each further comprise anaqueous solvent. In some embodiments, where the T1-reducing agent andthe T2-reducing contrast agent are administered to the patient as twoseparate compositions, the separate compositions can be administered inany order including but not limited to administering the T1-reducingcontrast agent followed by the T2-reducing contrast agent, administeringthe T2-reducing contrast agent followed by the T1-reducing contrastagent or administering the T1-reducing contrast agent and theT2-reducing contrast agent simultaneously. In some embodiments, the twoseparate compositions each further comprise an aqueous solvent.

In particular embodiments where the T1-reducing contrast agent and theT2-reducing contrast agent may be administered simultaneously, theT1-reducing contrast agent and the T2-reducing contrast agent may bemixed together as a dual-component solution before administration. Thedual-component solution may be composed of a mixture of two MRI contrastagents: a T2-reducing contrast agent that may be a large-particle agentthat reduces T2 (spin-spin relaxation time), and a T1-reducing contrastagent that may be a small-molecule agent that reduces T1 (spin-latticerelaxation time). The sizes of these two MRI contrast agents may be suchthat neither can pass through the lining of a healthy blood vessel, andonly the relatively small T1 or T2 agent can pass through the lining ofa diseased blood vessel. These two contrast agents may have oppositeeffects on MRI image intensity. The presence of the T2 contrast agentmay reduce local image intensity by causing a more rapid nuclear spindispersion, whereas the presence of the T1 contrast agent may increaselocal image intensity by allowing nuclear spins to more quicklyequilibrate between phase encoding repetitions. In some embodiments,administering the dual-component solution to a healthy blood vessel maycause the blood vessel lumen to go dark (the T2 effect may mask anypossible T1 effect). However, if a region of the blood vessel lining isselectively permeable to the smaller-sized T1 contrast agent, a brightsignal intensity may surround the blood vessel lumen. In otherembodiments, the dual-component solution may be composed of a mixture oftwo MRI contrast agents: a T1-reducing contrast agent that may be alarge-particle agent that reduces T1 (spin-lattice relaxation time), anda T2-reducing contrast agent that may be a small-molecule agent thatreduces T2 (spin-spin relaxation time). In some embodiments,administering the dual-component solution to a healthy blood vessel maycause the blood vessel lumen to go dark (the T2 effect may mask anypossible T1 effect). However, if a region of the blood vessel lining isselectively permeable to the smaller-sized T2 contrast agent, a brightsignal may be formed in the lumen due to diffusion of the smallerT2-reducing contrast agent into the luminal wall.

In some embodiments, the T1-reducing contrast agent reduces local T1(spin-lattice relaxation) time. In some embodiments, the T2-reducingcontrast agent reduces local T2 (Spin-Spin relaxation) time. In someembodiments, the T1-reducing contrast agent increases image signalintensity. In some embodiments, the T2-reducing contrast agent reducesimage signal intensity.

In some embodiments, the T2-reducing contrast agent is administered in aconcentration sufficient to mask the contrast effect of the T1-reducingcontrast agent within the lumen of the body cavity. In some embodiments,the T2-reducing contrast agent is administered in a concentrationsufficient to mask the contrast effect of the T1-reducing contrast agentwithin the lumen of the blood vessel.

In some embodiments, administering T1-reducing contrast agent and theT2-reducing contrast agent are completed simultaneously. In someembodiments, the T1-reducing contrast agent and the T2-reducing contrastagent may be combined into a single formulation prior to administration.In yet other embodiments, whether administered sequentially orsimultaneously, the T1-reducing contrast agent and T2-reducing contrastagent may be administered as separate formulations. In some embodiments,the T1-reducing contrast agent and T2-reducing contrast agent areadministered in a ratio of T1-reducing contrast agent to T2-reducingcontrast agent ranging from about 1 to 100 to about 100 to 1. In someembodiments, the T1-reducing contrast agent and T2-reducing contrastagent are administered in a ratio of T1-reducing contrast agent toT2-reducing contrast agent of about 1 to about 100, about 1 to about 50,about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1to about 10, about 1 to about 5, about 1 to about 1, about 1 to about12, or about 1 to about 11.76. In some embodiments, the ratio of theT1-reducing contrast agent to the T2-reducing contrast agent is suchthat the contrast effect of the T1-reducing contrast agent is masked bythe contrast effect of the T2-reducing contrast agent when administeredto the lumen of a body cavity. In some embodiments, the ratio of theT1-reducing contrast agent to the T2-reducing contrast agent is suchthat the contrast effect of the T1-reducing contrast agent is masked bythe contrast effect of the T2-reducing contrast agent when administeredto the lumen of a blood vessel.

In some embodiments, the T1-reducing contrast agent has a particle sizethat enables it to move out of lumen of a permeable body cavity. In someembodiments, the T1-reducing contrast agent has a particle size thatenables it to move out of lumen of a permeable blood vessel. In someembodiments, the T1-reducing contrast agent reduces local T1(spin-lattice relaxation) time. In some embodiments, the T2-reducingcontrast agent reduces local T2 (Spin-Spin relaxation) time. In someembodiments, the T1-reducing contrast agent increases image signalintensity. In some embodiments, the T2-reducing contrast agent reducesimage signal intensity. In some embodiments, the T2-reducing contrastagent is present in a concentration sufficient to mask the contrasteffect of the T1-reducing contrast agent within the lumen of a bodycavity. In some embodiments, the T2-reducing contrast agent is presentin a concentration sufficient to mask the contrast effect of theT1-reducing contrast agent within the lumen of a blood vessel. In someembodiments, the T2-reducing contrast agent has a particle size thatenables it to move out of lumen of a permeable body cavity. In someembodiments, the T2-reducing contrast agent has a particle size thatenables it to move out of lumen of a permeable blood vessel.

Embodiments herein are directed to methods for measuring thepermeability of a body cavity in a patient which may also be utilized tomap heterogeneity in the permeability of a body cavity. In someembodiments, the body cavity is a blood vessel. In some embodiments,where only a portion of the luminal wall of a body cavity is permeable,the T1-reducing contrast agent will diffuse into the permeable region ofthe luminal wall of the body cavity and a signal will be generated whichcan then be detected and will allow for identification of the permeableregion of the luminal wall. In some embodiments, the ability to mapheterogeneity may have utility in detecting lesions in a body cavity. Inparticular embodiments, the ability to map heterogeneity may haveutility in detecting diseased blood vessels. In some embodiments,diseased blood vessels may be characterized by a breakdown of theintercellular junctions of the vessel making the diseased blood vesselpermeable and allowing the T1-reducing contrast agent to diffuse intothe permeable region of the luminal wall of the diseased blood vessel.In some embodiments, the ability to map heterogeneity may have utilityin detecting PFO, ischemic endocardium, post-embolic or pre-hemorrhagicstroke breakdown of the blood-brain-barrier (BBB), vasculitis, rupturedatherosclerotic plaque, diabetic vasculopathy, inflammation, vasculitis,autoimmune disease, infection, cancer, septic shock, or a combinationthereof.

In some embodiments, imaging the patient comprises imaging via magneticresonance imaging. Imaging the patient may generally include imaging thepatient via a magnetic resonance process, such as, for example, magneticresonance processes now known or later developed. In some embodiments,imaging the patient comprises imaging via magnetic resonance imaging. Insome embodiments, imaging the patient comprises imaging via magneticresonance imaging. However, those having ordinary skill in the art willrecognize other imaging processes, such as, for example, x-ray imaging,computed tomography, positron emission scanning, and/or the like. Inaddition, those having ordinary skill in the art will recognize thatother contrast agents, imaging agents, and/or the like, may be usedalone or in combination with other contrast agents, imaging agentsand/or the like to measure the permeability of a body cavity using MRIor other imaging techniques known in the art. In some embodiments, oneor more contrast agents, imaging agents, and/or the like may be used ifthey possess a contrast effect that allows for measurement of thepermeability of a body cavity. In some embodiments, imaging the patientmay include imaging the patient for a period of time afteradministration of the T1-reducing contrast agent and the T2-reducingcontrast agent. In particular embodiments, the period of time maygenerally be a period of time that allows for diffusion of theT1-reducing contrast agent and/or the T2-reducing contrast agentadministered to the lumen of the body cavity. In some embodiments,imaging the patient is performed within about 10 minutes ofadministration of the T1-reducing contrast agent, T2-reducing contrastagent or combination thereof. In some embodiments, imaging the patientis performed within about 20 minutes of administration of theT1-reducing contrast agent, T2-reducing contrast agent or combinationthereof. In some embodiments, imaging the patient is performed withinabout 30 minutes of administration of the T1-reducing contrast agent,T2-reducing contrast agent or combination thereof. In some embodiments,imaging the patient is performed within about 30 minutes ofadministration of the T1-reducing contrast agent, T2-reducing contrastagent or combination thereof. In some embodiments, imaging the patientis performed within about 40 minutes of administration of theT1-reducing contrast agent, T2-reducing contrast agent or combinationthereof. In some embodiments, imaging the patient is performed withinabout 50 minutes of administration of the T1-reducing contrast agent,T2-reducing contrast agent or combination thereof. In some embodiments,imaging the patient is performed within about 60 minutes ofadministration of the T1-reducing contrast agent, T2-reducing contrastagent or combination thereof.

In some embodiments, the T1-reducing contrast agent may be a magneticresonance imaging (MRI) contrast agent. In some embodiments, the firstT1-reducing contrast agent comprises a gadolinium compound. In someembodiments, the gadolinium compound is selected from gadopentetatedimeglumine (Gd-DTPA), gadoterate meglumine, gadoversetamide,gadoteridol, gadodiamide, gadobenate dimeglumine, gadobutrol, gadoxetatedisodium, gadofosveset trisodium and combinations thereof. Those havingordinary skill in the art will recognize that othergadolinium-containing contrast agents and/or gadolinium salts that arenow known or later developed may also be used without departing from thescope of the present disclosure. In some embodiments the T1-reducingcontrast agent comprises Gadopentetate dimeglumine (Gd-DTPA). In someembodiments, the Gadopentetate dimeglumine (Gd-DTPA) is present in aconcentration of about 0.000425 M. In some embodiments, the gadoliniumcompound is encapsulated in liposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof. In some embodiments, the ironoxide is encapsulated in liposomes. In particular embodiments, theT2-reducing contrast agent may contain a plurality of magnetiteparticles. In some embodiments, the T2-reducing contrast agent comprisesferumoxytol. In some embodiments, the ferumoxytol is present in presentat a concentration of about 0.005M. In some embodiments, the iron oxideis encapsulated in liposomes.

In some embodiments, the T2-reducing contrast agent may contain aplurality of molecules, where the average diameter of the molecules isabout 100 Å to about 1000 Å. For example, the average diameter of themolecules in the T2-reducing contrast agent may be about 100 Å, about200 Å, about 300 Å, about 400 Å, about 500 Å, about 600 Å, about 700 Å,about 800 Å, about 900 Å, about 1000 Å, or any value or range betweenany two of these values (including endpoints).

In other particular embodiments, the T1-reducing contrast agents,T2-reducing contrast agents, or a combination thereof, may include oneor more of an iron oxide, iron platinum, manganese, and protein. Invarious embodiments, the MRI contrast agent may have an anionic neutralpH.

In some embodiments, the patient's body cavity is selected from theurinary bladder, the cardiovascular system, blood vessels, heart, lymphvessels, coelom, pericardial cavity, pericardium, intraembryonic coelom,extraembryonic coelom, chorionic cavity, dorsal cavity, ventral cavity,thoracic cavity, abdominopelvic cavity, cranial cavity, spinal cavity(or vertebral cavity), a pleural cavity, superior mediastinum, thoraciccavity, abdominal cavity, pelvic cavity. abdominopelvic cavity, kidneys,ureters, gastrointestinal tract, stomach, intestines, liver,gallbladder, pancreas, anus, reproductive system and any combinationthereof.

In some embodiments, the patient's body cavity is the cardiovascularsystem, blood vessels, heart, or combination thereof. In someembodiments, the patient is suspected of having PFO, ischemicendocardium, post-embolic or pre-hemorrhagic stroke breakdown of theblood-brain-barrier (BBB), vasculitis, ruptured atherosclerotic plaque,diabetic vasculopathy, inflammation, vasculitis, autoimmune diseases,infection, cancer, septic shock, or a combination thereof. In someembodiments, administration of the T1-reducing contrast agent and theT2-reducing contrast agent is achieved by administration into the lumenof the cardiovascular system, blood vessels, heart, or combinationthereof.

In some embodiments, the patient's body cavity is the gastrointestinaltract. In some embodiments, the patient is suspected of having acondition associated with the pathological breakdown of the layers ofepithelial cells and cell junctions that line the gastrointestinal tractincluding but are not limited to: inflammatory bowel disease,gastric/duodenal ulcer disease, celiac disease, or a combinationthereof. In some embodiments, administration of the T1-reducing contrastagent and the T2-reducing contrast agent is achieved by administrationinto the lumen of the gastrointestinal tract.

In some embodiments, a molecule or particle of T1-reducing contrastagents, T2-reducing contrast agents, or a combination thereof, may havea molecular weight of about 500 atomic mass units (amu) to about 1500amu. For example, the molecule or particle may have a molecular weightof about 500 amu, about 550 amu, about 600 amu, about 650 amu, about 700amu, about 750 amu, about 800 amu, about 850 amu, about 900 amu, about950 amu, about 1000 amu, about 1050 amu, about 1100 amu, about 1150 amu,about 1200 amu, about 1250 amu, about 1300 amu, about 1350 amu, about1400 amu, about 1450 amu, about 1500 amu, or any value or range betweenany two of these values (including endpoints). In a particularembodiment, the molecule or particle may have a molecular weight ofabout 938 amu.

In some embodiments, molecules or particles of the T1-reducing contrastagents, T2-reducing contrast agents, or a combination thereof, may havean average diameter of about 1 Angstrom (Å) to about 20 Å. For examplethe molecule may have a diameter of about 1 Å, about 2 Å, about 3 Å,about 4 Å, about 5 Å, about 6 Å, about 7 Å, about 8 Å, about 9 Å, about10 Å, about 11 Å, about 12 Å, about 13 Å, about 14 Å, about 15 Å, about16 Å, about 17 Å, about 18 Å, about 19 Å, about 20 Å, or any value orrange between any two of these values (including endpoints).

Table 1 displays the physical characteristics of T1-reducing contrastagents suitable for use in the present invention.

TABLE 1 Stock Molecular Average Brand Concentration Weight Diameter NameGeneric Name (M) (amu) (Å) Magnevist Gadopentetate 0.5 938.00 10dimeglumine (Gd-DTPA) Dotarem Gadoterate 0.5 753.86 9 meglumine OptiMARKGadoversetamide 0.5 661.77 8 ProHance Gadoteridol 0.5 558.70 7 OmniscanGadodiamide 0.5 573.66 8 MultiHance Gadobenate 0.5 1058.20 11Dimeglumine Gadovist Gadobutrol 1 604.70 8 Eovist Gadoxetate 0.25 725.729 Disodium Ablavar Gadofosveset 0.25 975.88 10 trisodium

Table 2 displays the physical characteristics of T2-reducing contrastagents suitable for use in the present invention.

TABLE 2 Stock Con- Molecular Average. centration Weight Diameter. BrandName Generic Name of Fe (M) (amu) (nm) Feraheme Ferumoxytol 0.537 n/a17-31 FeraSpin XS n/a 0.01 n/a 10-20 FeraSpin S n/a 0.01 n/a 20-30FeraSpin M n/a 0.01 n/a 30-40 FeraSpin L n/a 0.01 n/a 40-50 FeraSpin XLn/a 0.01 n/a 50-60 FeraSpin n/a 0.01 n/a 60-70 XXL FeraSpin R n/a 0.005n/a 10-90 n/a Iron nickel oxide n/a n/a <50 nanoparticle nanopowder n/aIron oxide(II, III) 0.018 to 0.09 n/a 4-6, 9-11, magnetic or 28-32nanoparticle dispersion/solution n/a Iron oxide(II, III) n/a n/a 4-6,9-11, magnetic or 28-32 nanopowder nanopowder n/a Iron nanopowder n/an/a 25, 35-45, 40-60, or 60-80 n/a Magnetic iron n/a n/a 3.5-9.5 oxidenanopowder

Some embodiments are directed to a method for measuring the permeabilityof a body cavity in a patient, the method comprising: administering acontrast agent with both T1-reducing and T2-reducing effects to thepatient; imaging the patient; and wherein diffusion of the solutionacross the luminal surface of the body cavity is indicative ofpermeability. In some embodiment, the body cavity is the cardiovascularsystem, blood vessels, heart, or a combination thereof. Some embodimentsare directed to a method for measuring the permeability of a body cavityin a patient, the method comprising: imaging the patient afteradministering a contrast agent with both T1-reducing and T2-reducingeffects to the patient; imaging the patient; and wherein diffusion ofthe contrast agent across the luminal surface of the body cavity isindicative of permeability. In some embodiment, the body cavity is thecardiovascular system, blood vessels, heart, or a combination thereof.In some embodiments, the contrast agent with both T1-reducing andT2-reducing effects comprises a gadolinium compound. In someembodiments, the contrast agent with both T1-reducing and T2-reducingeffects may be a magnetic resonance imaging (MRI) contrast agent. Inparticular embodiments, the contrast agent with both T1-reducing andT2-reducing effects may be a gadolinium-containing contrast agent. Insome embodiments, the gadolinium compounds include but are not limitedto gadopentetate dimeglumine (Gd-DTPA), gadoterate, gadoteratemeglumine, gadoversetamide, gadoteridol, gadodiamide, gadobenatedimeglumine, gadobutrol, gadoxetate disodium, gadofosveset trisodium,gadoteric acid, gadopentetate and combinations thereof. Those havingordinary skill in the art will recognize that othergadolinium-containing contrast agents and/or gadolinium salts that arenow known or later developed may also be used without departing from thescope of the present disclosure. In some embodiments the solutioncomprises Gadopentetate dimeglumine (Gd-DTPA). In some embodiments, theGadopentetate dimeglumine (Gd-DTPA) is present in a concentration ofabout 0.5 M. In some embodiments, administration of high concentrationsof a contrast agent with both T1-reducing and T2-reducing effects suchas, but not limited to, a gadolinium compound results in a reduction oflocal T1 (spin-lattice relaxation) time as well as a reduction of localT2 (Spin-Spin relaxation) time. In yet other embodiments, administrationof high concentrations of a contrast agent with both T1-reducing andT2-reducing effects such as, but not limited to, a gadolinium compoundresults in a reduction of image signal intensity. In some embodiments,administration of high concentrations of a contrast agent with bothT1-reducing and T2-reducing effects such as, but not limited to, agadolinium compound, is sufficient to mask the contrast effect of thecontrast agent with both T1-reducing and T2-reducing effects within thelumen of the body cavity. In some embodiments, masking of the contrasteffect of the contrast agent with both T1-reducing and T2-reducingeffects within the lumen of the body cavity indicative of anon-permeable body cavity. In yet other embodiments, diffusion of thecontrast agent with both T1-reducing and T2-reducing effects across theluminal surface of the bladder, or out of the lumen of the bladder, canbe visualized because of the reduction of local T2 (Spin-Spinrelaxation) time and masking of the contrast effect in the lumen of thebody cavity. In some embodiments, if the luminal wall of the body cavityis permeable, a bright ring will result due to diffusion of the contrastagent with both T1-reducing and T2-reducing effects into the tissue at aconcentration that is lower than in the lumen of the body cavity whichallows the T1-reducing effect of the contrast agent to dominate andcreate the bright ring image. In some embodiments, this is due to afiltering process. The contrast agent with both T1-reducing andT2-reducing effects remaining in the lumen of the body cavity remains ina concentration that is sufficiently high that the T2-reducing effectdominates and masks the signal.

Some embodiments are directed to a method for detecting the porosity ofthe luminal wall of a body cavity comprising: administering to the thelumen of the body cavity a T1-reducing contrast agent, a T2-reducingcontrast agent, wherein the particle size of the T2-reducing contrastagent are larger than the porosity of the luminal wall of the bodycavity; and wherein the particle size of the T1-reducing contrast agentis smaller than the porosity of the luminal wall of the body cavity,acquiring an MRI image of the body cavity and surrounding tissue,wherein the image is acquired such that tissues and fluids having low T2appear dark, tissues and fluids and fluids having low T1 appear bright,but however tissues and fluids having both low T1 and low T2 appeardark, and detecting if there is bright signal in said MRI imagecorresponding to tissue surrounding said cavity. In some embodiment, thebody cavity is the cardiovascular system, blood vessels, heart, or acombination thereof.

In various embodiments, a method of performing a diagnostic examinationof a patient's cardiovascular system, blood vessels, heart, or acombination thereof may include, but is not limited to, providing aT1-reducing contrast agent to the cardiovascular system, blood vessels,heart, or a combination thereof of a patient, providing a T2-reducingcontrast agent to the cardiovascular system, blood vessels, heart, or acombination thereof of the patient, and imaging the patient. In someembodiments, the patient is suspected of having PFO, ischemicendocardium, post-embolic or pre-hemorrhagic stroke breakdown of theblood-brain-barrier (BBB), vasculitis, ruptured atherosclerotic plaque,diabetic vasculopathy, inflammation, vasculitis, autoimmune disease,infection, cancer, septic shock, or a combination thereof withoutwishing to be bound by theory, certain diseases, including, but notlimited to, the conditions described herein result in a breakdown of theintercellular junctions of the blood vessel making the diseased bloodvessel permeable and allowing the T1-reducing contrast agent to diffuseinto the permeable region of the luminal wall of the diseased bloodvessel.

In some embodiments, the solutions, compositions, and methods disclosedherein can be utilized with or on a subject in need of such treatment,which can also be referred to as “in need thereof.” As used herein, thephrase “in need thereof” means that the subject has been identified ashaving a need for the particular method or treatment and that thetreatment has been given to the subject for that particular purpose.

In some aspects, the invention is directed to an imaging compositioncomprising one or more solutions, as defined herein, and, in someembodiments, a pharmaceutically acceptable carrier or diluent, or aneffective amount of a pharmaceutical composition comprising a solutionas defined above.

Some embodiments are directed to imaging compositions comprising: aT1-reducing contrast agent; and a T2-reducing contrast agent, whereinthe T2-reducing contrast agent. In some embodiments, the imagingcomposition further comprises an aqueous solution. In some embodiments,the particle size of the T2-reducing contrast agent is larger than theparticle size of the T1-reducing contrast agent.

In some embodiments, the T1-reducing contrast agent comprises agadolinium compound. In some embodiments, the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof. In some embodiments, the gadolinium compound is encapsulated inliposomes.

In some embodiments, the T2-reducing contrast agent comprises an ironoxide. In some embodiments, the iron oxide is selected from iron (II)oxide, iron (III) oxide, ferumoxytol (Feraheme), Feraspin XS, FeraspinS, Feraspin M, Feraspin R, Feraspin L, Feraspin XL, iron nickel oxidenanopowder, iron oxide (II,III) magnetic nanoparticles, iron-nickelalloy nanopowder, magnetic iron oxide nanoparticles, carbon coated ironnanopowder, and combinations thereof. In some embodiments, the ironoxide is encapsulated in liposomes.

In some embodiments, the methods and compositions described herein maycomprise other contrast agents that when administered together, oralone, exhibit a contrast effect that allows measurement of thepermeability of a body cavity. In some embodiments, these contrastagents may be useful for measuring body cavity permeability using MRI aswell as imaging techniques other than MRI.

The contrast agents and compositions of the present invention can beadministered in the conventional manner by any route where they areactive. Administration can be systemic, topical, or oral or viainstillation. For example, administration can be, but is not limited to,parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal,transdermal, oral, buccal, or ocular routes, or intravaginally, byinhalation, by depot injections, or by implants. Thus, modes ofadministration for the compositions and solutions of the presentinvention (either alone or in combination with other pharmaceuticals)can be, but are not limited to, instillation, sublingual, injectable(including short-acting, depot, implant and pellet forms injectedsubcutaneously or intramuscularly), or by use of vaginal creams,suppositories, pessaries, vaginal rings, rectal suppositories,intrauterine devices, and transdermal forms such as patches and creams.

Specific modes of administration will depend on the indication or bodycavity being imaged. The selection of the specific route ofadministration and concentration of imaging compositions containing theT1-reducing contrast agents, T2-reducing contrast agents, orcombinations thereof, is to be adjusted or titrated by the clinicianaccording to methods known to the clinician in order to optimize theimaging process. The concentration to be administered will depend on thecharacteristics of the patient to which the contrast agent, contrastagents, or compositions being administered, e.g., the particular patient(human or animal) treated, age, weight, health, types of concurrenttreatment, if any, and frequency of treatments, and can be easilydetermined by one of skill in the art (e.g., by the clinician).

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, of the presentinvention and a suitable carrier can be solid dosage forms whichinclude, but are not limited to, tablets, capsules, cachets, pellets,pills, powders and granules; topical dosage forms which include, but arenot limited to, solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels and jellies, and foams; andparenteral dosage forms which include, but are not limited to,solutions, suspensions, emulsions, and dry powder; comprising aneffective amount of a polymer or copolymer of the present invention. Itis also known in the art that the active ingredients can be contained insuch formulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, can be formulatedfor instillation. The agents and compositions can be administered byinstillation over a period of about 15 minutes to about 24 hours.Formulations for instillation can be presented in unit dosage form,e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, can be formulatedfor parenteral administration by injection, e.g., by bolus injection orcontinuous infusion. The agents and compositions can be administered bycontinuous infusion subcutaneously over a period of about 15 minutes toabout 24 hours. Formulations for injection can be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

For oral administration, the Imaging compositions containing theT1-reducing contrast agents, T2-reducing contrast agents, orcombinations thereof, can be formulated readily by combining the agentsdescribed herein with pharmaceutically acceptable carriers well known inthe art. Such carriers enable the agents of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a patient tobe treated. Imaging preparations for oral use can be obtained by addinga solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations such as, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active doses.

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, which can be usedorally include, but are not limited to, push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. The push-fit capsules cancontain the agents in admixture with filler such as, e.g., lactose,binders such as, e.g., starches, and/or lubricants such as, e.g., talcor magnesium stearate and, optionally, stabilizers. In soft capsules,the agents can be dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers can be added. All formulations for oraladministration should be in dosages suitable for such administration.For buccal administration, the solutions can take the form of, e.g.,tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the Imaging compositions containingthe T1-reducing contrast agents, T2-reducing contrast agents, orcombinations thereof, for use according to the present invention areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, of the presentinvention can also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In some embodiments, the Imaging compositions containing the T1-reducingcontrast agents, T2-reducing contrast agents, or combinations thereof,may be prepared as suspensions, solutions or emulsions in oily oraqueous vehicles suitable for injection. In such embodiments, suchsolutions may further include formulatory agents such as suspending,stabilizing and or dispersing agents formulated for parenteraladministration. Such injectable solutions may be administered by anyroute, for example, instillation, subcutaneous, intravenous,intramuscular, intra-arterial or bolus injection or continuous infusion,and in embodiments in which injectable compositions are administered bycontinuous infusion, such infusion may be carried out for a period ofabout 15 minutes to about hours. In certain embodiments, compositionsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative.

In some embodiments, the Imaging compositions containing the T1-reducingcontrast agents, T2-reducing contrast agents, or combinations thereof,described herein may be encapsulated in liposomes. The liposomes may beused to increase the size of the agents. The liposomes may be preparedby a variety of methods. In the process of making liposomes, the agentsmay be added at any desired time. For example, agents may be associatedwith components of liposomes before liposomes are formed. Agents may becombined with liposome components at the time the liposomes are made.Agents may also be added after the liposomes are formed. Other methodsof associating agents with liposomes may exist. Generally, agents whichare hydrophilic in nature may be located or associated with the internalcavity of the liposome particles. Agents which are lipophilic in naturemay be located or associated with the lipid bilayer of liposomeparticles. Generally, the agents herein are located or associated withthe internal cavity of the liposome.

There are a variety of methods for encapsulating the Imagingcompositions containing the T1-reducing contrast agents, T2-reducingcontrast agents, or combinations thereof, described herein into theliposomes. The method may include selecting one or more agents to beused. The method may also include forming liposomes in the presence ofthe one or more agents. In some embodiments, these methods may includehydration of dried lipids, introduction of a volatile organic solutionof lipids into an aqueous solution causing evaporation of the organicsolution, dialysis of an aqueous solution of lipids and detergents orsurfactants to remove the detergents or surfactants, and others. In someembodiments, the agents encapsulated in liposomes may be manufactured byco-dissolving sphingomyelin with the agent in a 30% tertiary butylalcohol-water solvent then lyophilized. This procedure will generate apre-liposomal lyophilate of the agent with particle sizes that rangefrom about 1 μm to about 50 μm diameters. Upon rehydration, a standardmultiple dialysis technique will be used to isolate specific size rangesof the agents encapsulated in the liposomes.

In addition to the formulations described herein, the Imagingcompositions containing the T1-reducing contrast agents, T2-reducingcontrast agents, or combinations thereof, of the present invention canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection.

Depot injections can be administered at about 1 to about 6 months orlonger intervals. Thus, for example, the compounds can be formulatedwith suitable polymeric or hydrophobic materials (for example as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, for example, as a sparingly soluble salt.

In transdermal administration, the compounds of the present invention,for example, can be applied to a plaster, or can be applied bytransdermal, therapeutic systems that are consequently supplied to theorganism.

Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, described hereinalso can comprise suitable solid or gel phase carriers or excipients.Examples of such carriers or excipients include but are not limited tocalcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and polymers such as, e.g., polyethyleneglycols.

The Imaging compositions containing the T1-reducing contrast agents,T2-reducing contrast agents, or combinations thereof, of the presentinvention can also be formulated and/or administered in combination withother active ingredients, such as, for example, adjuvants, proteaseinhibitors, or other compatible drugs or compounds where suchcombination is seen to be desirable or advantageous in achieving thedesired effects of the methods described herein.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification.

1. A method for detecting patent foramen ovale in a patient comprising:administering a T1-reducing contrast agent and a T2-reducing contrastagent to the patient; and imaging the patient's heart; wherein diffusionof the T2 reducing contrast agent from the right atrium to the leftatrium is indicative of patent foramen ovale.
 2. The method of claim 1,wherein the particle size of the T2-reducing contrast agent is largerthan the particle size of the T1-reducing contrast agent
 3. The methodof claim 1, wherein the T1-reducing contrast agent and the T2-reducingcontrast agent are administered to the patient as a single composition.4. The method of claim 1, wherein the T1-reducing agent and theT2-reducing contrast agent are administered to the patient as twoseparate compositions.
 5. The method of claim 1, wherein administeringT1-reducing contrast agent and the T2-reducing contrast agent arecompleted simultaneously.
 6. The method of claim 1, wherein imaging thepatient's heart comprises imaging via magnetic resonance imaging.
 7. Themethod of claim 1, wherein imaging the patient's heart is performedwithin about 10 minutes of administration of the T1-reducing contrastagent and the T2-reducing contrast agent.
 8. The method of claim 1,wherein the first T1-reducing contrast agent comprises a gadoliniumcompound.
 9. The method of claim 8, wherein the gadolinium compound isselected from gadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof.
 10. The method of claim 1, wherein the T2-reducing contrastagent comprises an iron oxide.
 11. The method of claim 10, wherein theiron oxide is selected from iron (II) oxide, iron (III) oxide,ferumoxytol (Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder, magneticiron oxide nanoparticles, carbon coated iron nanopowder, andcombinations thereof.
 12. The method of claim 1, wherein administrationof the T1-reducing contrast agent and the T2-reducing contrast agent isachieved by administration to the patient's cardiovascular system.
 13. Amethod for detecting patent foramen ovale in a patient comprising:imaging the patient after administering a T1-reducing contrast agent anda T2-reducing contrast agent to the patient; wherein diffusion of the T2reducing contrast agent from the right atrium to the left atrium isindicative of patent foramen ovale.
 14. The method of claim 13, whereinthe particle size of the T2-reducing contrast agent is larger than theparticle size of the T1-reducing contrast agent.
 15. The method of claim13, wherein the T1-reducing contrast agent and the T2-reducing contrastagent are administered to the patient as a single composition.
 16. Themethod of claim 13, wherein the T1-reducing contrast agent and theT2-reducing contrast agent are administered to the patient as twoseparate compositions.
 17. The method of claim 13, wherein administeringT1-reducing contrast agent and the T2-reducing contrast agent arecompleted simultaneously.
 18. The method of claim 13, wherein imagingthe patient comprises imaging via magnetic resonance imaging.
 19. Themethod of claim 13, wherein imaging the patient is performed withinabout 10 minutes of administration of the T1-reducing contrast agent andthe T2-reducing contrast agent.
 20. The method of claim 13, wherein thefirst T1-reducing contrast agent comprises a gadolinium compound. 21.The method of claim 20, wherein the gadolinium compound is selected fromgadopentetate dimeglumine (Gd-DTPA), gadoterate meglumine,gadoversetamide, gadoteridol, gadodiamide, gadobenate dimeglumine,gadobutrol, gadoxetate disodium, gadofosveset trisodium and combinationsthereof.
 22. The method of claim 13, wherein the T2-reducing contrastagent comprises an iron oxide.
 23. The method of claim 22, wherein theiron oxide is selected from iron (II) oxide, iron (III) oxide,ferumoxytol (Feraheme), Feraspin XS, Feraspin S, Feraspin M, Feraspin R,Feraspin L, Feraspin XL, iron nickel oxide nanopowder, iron oxide(II,III) magnetic nanoparticles, iron-nickel alloy nanopowder, magneticiron oxide nanoparticles, carbon coated iron nanopowder, andcombinations thereof.
 24. The method of claim 13, wherein administrationof the T1-reducing contrast agent and the T2-reducing contrast agent isachieved by administration to the patient's cardiovascular system.25.-48. (canceled)